An unexpected pentacarbonyl chromium complexation of a cyano group of the ABC core of cephalotaxine
Graphical abstract
Contrary to safrole which reacts with chromium carbonyl to give the expected arene tricarbonyl chromium species, its derivative bearing an enamino-nitrile function leads, in the presence of transfer agents, [Cr(CO)3(naphthalene)] or [Cr(CO)3(tmtach)], to a pentacarbonyl chromium complex at the electron rich nitrile nitrogen atom.
Introduction
The biological activity of a number of ester derivatives of cephalotaxine (1) is remarkable, as illustrated by homoharringtonine (HHT) (2) (Omacetaxine mepesuccinate® (Fig. 1) [1]. HHT (2) has an IC50 of 0.017 μg/mL against the cell line P-388 [2] and demonstrated clinical activity in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) through binding to the ribosome thus inhibiting protein synthesis [3] and promoting cell death by apoptosis [4]. The activity of HHT (2) has been demonstrated by more than 50 clinical studies, primarily sponsored by the National Cancer Institute (NCI) in the United States, and in China. HHT (2) is used for the treatment of leukemia in China and has received its approval in Europe as an orphan drug and was approved by the FDA in October 2012 as a treatment for acute myeloid leukemia for patients who are resistant to two tyrosine kinase inhibitors [5]. Thanks to this clinical importance, and due to its unique pentacyclic structure, the alkaloid core cephalotaxine (1) became an attractive target for the chemists. Since the publication of its first synthesis by Weinreb and Semmelhack in 1972 [6], 24 racemic syntheses, 19 enantioselective syntheses of (−)-cephalotaxine (natural configuration) and one of the (+)-enantiomer have been published [7].
In our attempt to complete the total synthesis of (−)-cephalotaxine 1, the tetracyclic pyrrolobenzazepine unit 3, which could be regarded as a potential precursor of cephalotaxine 1 missing only two carbon atoms (C1–C2) of elaboration of the D ring, was prepared with a 16.2% overall yield in a concise eight-step sequence from inexpensive safrole [8]. However, nucleophilic addition to this compound, a prerequisite to the formation of the D ring of 1, was not possible [9]. This unexpected reactivity was explained by the almost null partial charges at C3 and C5 positions, which were accurately determined experimentally by high-resolution X-ray diffraction studies at 100 K. We have therefore envisaged the substitution of the A ring by an electron withdrawing chromium tricarbonyl substituent to reverse this unusual electronic distribution (Fig. 2), hoping that this would allow the addition of a nucleophile bringing the two missing carbon atoms needed to complete the D cycle of the cephalotaxine 1 skeleton.
Indeed, the neutral [(η6-arene)Cr(CO)3] motif has been taking a growing place in organometallic chemistry as well as in organic synthesis [10]. The electrophilicity of an arene is dramatically enhanced by coordination to a tricarbonyl metal entity (M(CO)3; M = Cr, Mn+), allowing several transformations which cannot be carried out on the metal-free arene ring. Thus there has been widespread interest in the chemistry of arene-metal complexes and, among them, (η6-ArH)Cr(CO)3 complexes have been extensively studied [11], [12], [13], [14]. These complexes are used in many synthetic applications including diastereoselective and enantioselective synthesis, chiral ligand design [15], [16] and total synthesis [17]. In particular, it has been shown that nucleophilic attack of Cr(CO)3 substituted arenes bearing a conjugated double bond led to a stabilized benzyl anion through addition of the nucleophile at the β position [18], [19], [20], [21].
We report herein on the unexpected results dealing with the formation of a pentacarbonyl chromium carbonyl species starting from tetracyclic pyrrolobenzazepine unit 3.
Section snippets
Preparation of the organic ligand 3
Compound 3 was synthesized from safrole 5 in a concise eight-step sequence with an overall yield of 16.2% (Scheme 1).
The synthesis of compound 6 was accomplished by reductive ozonolysis of the vinylic side chain terminus of safrole 5 [22]. Nucleophilic substitution of the resulting alcohol function by bromine yielded 7 in 72.8% yield from safrole (2 steps). The C ring of cephalotaxine 1 was introduced by nucleophilic substitution of the bromide atom of 7 by the sodium salt of succinimide
Conclusion
In order to modify the reactivity of a pyrrolobenzazepine unit toward nucleophilic attack, we envisaged its transformation into an arene chromium tricarbonyl complex. Unexpectedly, the reaction conditions used led to a chromium pentacarbonyl complex where the metal was linked to the nitrogen atom of the organic framework. The study of the nucleophilic attack of this complex is now under progress and will be reported in due course.
General
TLC analyses were carried out on aluminum sheets precoated with silica gel (60 F254) and visualized with UV light, staining at 100 °C was performed using Kägi–Misher reagent. Purification by column chromatography was performed using 70–230 mesh silica gel (Merck). NMR spectra were recorded with a Bruker Advance DRX 500 FT spectrometer [400 MHz (1H) and 100 MHz (13C)] or a Bruker AH 300 FT spectrometer [300 MHz (1H) and 75 MHz (13C)]. Chemical shifts are expressed in ppm downfield from TMS. Data
Acknowledgments
The authors thank P Kündig (University of Geneva, Switzerland) for a gift of naphthalene chromium complex, Dr Françoise Rose-Munch (University P & M Curie, Paris, France) and Pr Khalil Asali (Jordan University of Science & Technology, Irbid, Jordan) for stimulating scientific discussions, Dr Joseph Ferrara (Rigaku Americas Corporation) for great help in twin deconvolution regarding data collected from the crystallized compound 13, Estelle Morvan (Faculty of Pharmacy, Châtenay-Malabry, France)
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6.05 - Group VI Metal Complexes of Carbon Monoxide and Isocyanides
2022, Comprehensive Organometallic Chemistry IV: Volume 1-15